EP0016310B1 - Monophosphonate compounds, process for their preparation and pharmaceutical compositions containing them - Google Patents

Monophosphonate compounds, process for their preparation and pharmaceutical compositions containing them Download PDF

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Publication number
EP0016310B1
EP0016310B1 EP80100295A EP80100295A EP0016310B1 EP 0016310 B1 EP0016310 B1 EP 0016310B1 EP 80100295 A EP80100295 A EP 80100295A EP 80100295 A EP80100295 A EP 80100295A EP 0016310 B1 EP0016310 B1 EP 0016310B1
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EP
European Patent Office
Prior art keywords
formula
compounds
compound
alkylphosphonate
monophosphonate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP80100295A
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German (de)
English (en)
French (fr)
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EP0016310A1 (en
Inventor
Lan Nguyen Mong
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Symphar SA
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Symphar SA
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3882—Arylalkanephosphonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4025—Esters of poly(thio)phosphonic acids

Definitions

  • the present invention relates to new monophosphonate compounds, and more particularly to halogenophenylalkylphosphonates and to halogenophenoxyalkylphosphonates, as well as to a process for their preparation and to pharmaceutical compositions containing these compounds.
  • phosphorus compounds have been previously shown to demonstrate hypoglycemic activity, for example phenacyltriphenylphosphoranes and phosphonium salts as described in "J. Medicinal Chemistry” 18(9), 952 (1975). More recently, Parker et al. published on the synthetic steroid inhibitory action of alkylphosphonates and phosphonophosphates in "Biochimica et Biophysica Acta” 530, 24 (1978).
  • halogenophenylalkylphosphonates and halogenophenoxyalkylphosphonates of formula (I) possess remarkable activity as hypoglycemic and/or antiartherogenic agents, as well as the ability to alter lipoprotein profiles in favour of high density lipoproteins, and to clear cholesterol from various tissues.
  • R is ⁇ P0 3 Me 2 , ⁇ P0 3 Et 2 , ⁇ P0 3 H 2 or -P0 3 Na 2
  • X is a halogen, preferably chlorine, in position o, m or p, preferably in position p; m is 0 or 1; and n is 2, 3, 4, 5 or 6.
  • halogenophenoxyalkylphosphonate compounds of formula (ta) and halogenophenylalkyl- phosphonate compounds of formula (lb), where R, n and X are as defined above can be prepared according to the following scheme: where m is 0 or 1, Y is CI or Br and Z is Me or Et.
  • a mixture of 50 g (0.20 mot) of 3(p-chlorophenoxy)propylbromide (prepared according to the same method referred to in Example 1) and 77.4 g (0.47 mol) of triethyl phosphite was refluxed at 160° for seven and a half hours. During this period the circulating water in the condenser was maintained at 50° by means of a thermoregulated bath to ensure the complete removal of the ethyl bromide evolved (bp: 38°). After the excess of triethyl phosphite was removed under reduced pressure, the residue was distilled under high vacuum to give 55 g (0.18 mol) of a white viscuous oil.
  • Compound 7 was transformed into its di-sodium salt, according to the following procedure: 1.5 g (6 mmol) of Compound 7 dissolved in 12 ml of methanol was added a solution of 0.48 g (12 mmol) of sodium hydroxide in 6 ml 80% methanol. The mixture was evaporated to dryness and the white residue recrystallized in a water:ethanol 1:1 mixture. 1 .8 g (100%) of the disodium salt of 3(p-chlorophenoxy)-propylphosphonic acid was thus recovered.
  • mice Male Wistar rats (4-5/group) weighing 150 to 200 g were treated for 4 days with compound 4 or the respective vehicle.
  • the lipid soluble monophosphonate was solubilized in corn oil and administered by gastric intubation (at a dosage of 50 mg/kg), corn oil alone being used as control.
  • the rats were fasted overnight and sacrificed the 5th day by decapitation under light ether anesthesia.
  • Blood samples were collected using E.D.T.A. as anticoagulant.
  • the livers, epididymal fat pads and aortas were weighted and stored at -20 0 C until utilized for lipid extraction.
  • Glucose concentration was determined by the enzymatic method of Werner, W., H.G. and Wielinger, (Z. Analyt. Chem. 252, 224, 1970) (glucose oxidase-peroxidase) obtained from Boehringer Mannheim (nr 124036).
  • Fresh plasma lipoproteins were stained with sudan-black and analysed by electrophoresis using polyacrylamide gels according to Frings, G.S. et al. (Clinical Chemistry, 17, 111, 1971).
  • the separated high density lipoproteins (HDL), low density lipoproteins (LDL) and very low density lipoproteins (VLDL) were quantitated by densitometric tracings of the gels.
  • control and treated animals were previously given p.o. a cholesterol supplement of 160 mg/kg per day for two weeks prior to and during treatment with compound 4.
  • Lipids were extracted from livers and epididymal fat pads according to J. Folch et al (J. Biol. Chem. 226, 497, 1957) and the cholesterol content of the extracts was determined by the Liebermann-Burchard reaction (Chem. Ber. 18, 1803, 1885 and Chem. Ber..61, 25, 1890).
  • Compound 4 significantly decreases blood glucose by 32%, increases the lipoprotein ratio HDL/LDL+VLDL by 108%, and decreases liver cholesterol by 18% and epididymal fat pad cholesterol by 46%, with regard to the control values.
  • compounds (I) produce a remarkable hypoglycemic activity and increase the quantity of circulating high density lipoproteins.
  • these compounds (I) have the ability to clear cholesterol from various tissues even in the presence of exogenously added cholesterol to the diet.
  • phosphonate compound Safe and effective amounts of phosphonate compound are prepared in sufficient amounts to produce a desirable effect at a reasonable benefit/risk ratio attendant with any medical treatment.
  • dosage of phosphonate compound will vary with the particular condition being treated, the severity of the conditions, the duration of the treatment, and the specific phosphonate compound employed.
  • the phosphonates are prepared as pharmaceutically acceptable products which include all ingredients used in the compositions employed and are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response commensurate with a reasonable benefit/risk ratio.
  • compositions according to the present invention for oral unit dosage forms can be a mixture with a solid vehicule containing lactose, saccharose, sorbitol, mannitol, amidon, amylopectine, cellulose derivative, and/or gelatine which can be prepared with the lubricants such as magnesium stearate, calcium stearate, forms of "carbowax" and/or polyethylene glycol. It can be preferable in some cases to use a capsule, and the ingredients can then consist of a mixture containing concentrated sugar, arabic gum, talc, and/or titan bioxide.
  • particular phosphonates can be mixed in buffer solution, corn oil, olive oil, glycerol commercial fillers, and administered in a closed hard gelatin capsule, as drops, or sirop forms.
  • the phosphonates can be fabricated with "Imhausen H" to produce suitable suppositories.
  • Compound 4 was compressed in tablet form with magnesium stearate 10% and starch 25% to obtain a final concentration of about 50 to 250 mg active agent.
  • compounds of formula (I) can be used up in solution of drinking water or corn oil at concentrations between about 2 mg/ml and 100 mg/ml.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP80100295A 1979-02-13 1980-01-22 Monophosphonate compounds, process for their preparation and pharmaceutical compositions containing them Expired EP0016310B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB7904992A GB2043073B (en) 1979-02-13 1979-02-13 Mono-and diphosphonate compounds
GB7904992 1979-02-13

Publications (2)

Publication Number Publication Date
EP0016310A1 EP0016310A1 (en) 1980-10-01
EP0016310B1 true EP0016310B1 (en) 1982-09-22

Family

ID=10503154

Family Applications (1)

Application Number Title Priority Date Filing Date
EP80100295A Expired EP0016310B1 (en) 1979-02-13 1980-01-22 Monophosphonate compounds, process for their preparation and pharmaceutical compositions containing them

Country Status (6)

Country Link
US (1) US4268507A (cg-RX-API-DMAC10.html)
EP (1) EP0016310B1 (cg-RX-API-DMAC10.html)
JP (2) JPS55111494A (cg-RX-API-DMAC10.html)
DE (1) DE3060861D1 (cg-RX-API-DMAC10.html)
GB (1) GB2043073B (cg-RX-API-DMAC10.html)
ZA (1) ZA80688B (cg-RX-API-DMAC10.html)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4456464A (en) * 1982-05-19 1984-06-26 Zoecon Corporation Phenoxy- and pyridyloxy-phenoxyalkyl phosphinates and related sulfur compounds for weed control
DE3203308A1 (de) * 1982-01-27 1983-07-28 Schering Ag, 1000 Berlin Und 4619 Bergkamen Diphosphonsaeure-derivate und diese enthaltende pharmazeutische praeparate
US4536355A (en) * 1982-10-08 1985-08-20 Zoecon Corporation Phenoxyphenylaminoalkylphosphinates useful in weed control
US4556520A (en) * 1982-10-08 1985-12-03 Zoecon Corporation 2-Nitro(cyano)phenyloxy(thio)alkyl phosphinates or phosphonates
HU190579B (en) * 1984-07-18 1986-09-29 Nitrokemia Ipartelepek,Hu Plant growth regulating compositions comprising etherified hydroxy-alkyl-phosphonic acid-derivatives as active substance
JPH0651625B2 (ja) * 1986-12-29 1994-07-06 株式会社大塚製薬工場 高脂質血症治療剤
US4822780A (en) * 1987-07-08 1989-04-18 Otsuka Pharmaceutical Factory, Inc. Carboxamide compounds
US4992429A (en) * 1989-08-24 1991-02-12 Rhone-Poulenc Rorer Pharmaceuticals Inc. Novel HMG-COA reductase inhibitors
US5264607A (en) * 1991-09-30 1993-11-23 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Process of making benzylic α,α-diflurophosphonates from benzylic α-ketophosphorates
JPH06172372A (ja) * 1991-11-06 1994-06-21 Takeda Chem Ind Ltd スクアレン合成酵素阻害剤およびその用途
CN1060480C (zh) * 1997-04-30 2001-01-10 华中师范大学 具有除草活性的取代苯氧乙酰氧基烃基膦酸酯及制备
ATE350385T1 (de) * 2000-03-08 2007-01-15 Metabasis Therapeutics Inc Neue aryl fructose-1,6-bisphosphatase inhibitoren
US7435841B2 (en) 2004-03-10 2008-10-14 Rhodia Inc. Preparation of halohydrocarbyl phosphonic acid diesters
EP2417142B1 (en) * 2009-04-06 2014-07-23 Georgia Tech Research Corporation Electronic devices comprising novel phosphonic acid surface modifiers

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE519738A (cg-RX-API-DMAC10.html) * 1952-05-07
GB751755A (en) * 1952-12-08 1956-07-04 Henkel & Cie Gmbh Substituted methane-phosphonic acids and derivatives thereof
GB777718A (en) * 1953-04-20 1957-06-26 Ciba Ltd New organic compounds containing phosphorus and process for making them
US3524846A (en) * 1967-06-02 1970-08-18 Syntex Corp Process for the didealkylation of phosphonate esters
GB1366600A (en) * 1971-11-16 1974-09-11 Scottish Agricultural Ind Ltd Amine salts of organo phosphorus acids
SE7407373L (cg-RX-API-DMAC10.html) * 1973-06-22 1974-12-23 Ciba Geigy Ag
US3984501A (en) * 1975-02-03 1976-10-05 Nelson Research & Development Company Phenyl- and benzylphosphonate esters
US4182759A (en) * 1978-06-05 1980-01-08 Sterling Drug Inc. Arylalkyl and aryloxyalkyl phosphonates and use as antiviral agents

Also Published As

Publication number Publication date
US4268507A (en) 1981-05-19
EP0016310A1 (en) 1980-10-01
GB2043073A (en) 1980-10-01
ZA80688B (en) 1981-02-25
GB2043073B (en) 1983-05-11
DE3060861D1 (en) 1982-11-04
JPS55111495A (en) 1980-08-28
JPH0122277B2 (cg-RX-API-DMAC10.html) 1989-04-25
JPS55111494A (en) 1980-08-28

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